PROJECT SUMMARY Bone morphogenetic proteins (BMP) are highly expressed in lung cancer cells promoting survival and distant spread. Increased BMP expression also occurs in the brain with natural aging and is accelerated in Alzheimer?s disease (AD). BMP promotes the differentiation of adult neural stem cells (NSC) into astroglial cells and suppresses their differentiation into neurons, which are required for memory and cognition. Inhibition of the BMP receptors promotes the regeneration of new neurons and improves cognition in aging mice and mouse models of AD. In our parent R01, we are developing BMPR2 inhibitors for the treatment of lung cancer. We have developed significantly more specific BMPR2 inhibitors. We find that inhibition of BMPR2 causes potent inhibition of mechanistic target of rapamycin 1 (mTORC1), mTORC2, and Akt. Furthermore, these novel BMPR2 inhibitors cause the activation of AMP-activated protein kinase (AMPK). The inhibition of mTOR and the activation of AMPK have not only been shown to suppress tumor growth but this same regulatory signature has been shown to increase longevity and to decrease neurodegenerative diseases. Targeting BMPR2 represents a novel strategy to treat AD and other neurodegenerative diseases by promoting neurogenesis. Neurodegenerative diseases and cancer are diseases of aging. The ability to slow the aging process is a potential way to significantly delay the onset of neurodegenerative diseases, cancer, and cardiovascular disease. Limiting caloric intake has been shown to increase longevity and impact the development and treatment of age-related diseases including AD. The cellular response to caloric restriction (CR) is dependent on the activation of AMPK and suppression of mTOR signaling, which is the same regulatory signature induced by our BMPR2 inhibitors. A drug that can induce the biologic response mimicking CR could have a major impact on age-related diseases. We hypothesize that BMPR2 inhibition with small molecules can be used to treat neurodegenerative diseases and cancer, which involves the suppression of mTOR and the activation of AMPK. We have established a team of scientists with expertise in BMP biology, BMP receptor trafficking, neuroscience, medicinal chemistry, computational biology, neural pathology, and crystallography who together, are uniquely qualified to successfully complete the following specific aims. Aim 1: Determine in SAMP8 mouse models of Alzheimer?s disease, the effects of our new generation of BMPR2 inhibitors engineered to cross the blood-brain barrier on NSC neurogenesis, synaptic and dendritic integrity, and astrocyte senescence. Aim 2: Determine in C. elegans the regulation of AMPK and mTOR with BMPR2 during starvation. Examine whether AMPK and mTOR regulate daf-4(BMPR2) trafficking during starvation.